Upconversion nanoparticles (UCNPs) have recently emerged as a new class of materials with potential applications in a wide-range of fields, such as biosensing, chemical sensing, in vivo imaging, drug delivery, photodynamic therapy and photoactivation. (Zhan, et al. 2011 Acs Nano 5, 3744; Wang, et al. 2005 Angew Chem Int Edit 44, 6054; Achatz, et al. 2011 Angew Chem Int Edit 50, 260; Liu, et al. 2011 Acs Nano 5, 8040; Liu, et al. 2011 J Am Chem Soc 133, 17122; Chen, et al. 2012 Acs Nano 6, 8280; Lim, et al. 2006 Nano Lett 6, 169; Wang, et al. 2011 Biomaterials 32, 1110; Hou, et al. 2011 Adv Funct Mater 21, 2356; Tian, et al. 2012 Adv Mater 24, 1226; Shan, et al. 2011 Adv Funct Mater 21, 2488; Zhang, et al. 2007 J Am Chem Soc 129, 4526; Jayakumar, et al. 2012 Natl Acad Sci USA 109, 8483; Yang, et al. 2012 Angew Chem Int Edit 51, 3125; Yan, et al. 2012 J Am Chem Soc 134, 16558; U.S. Pat. No. 7,332,344; U.S. Pat. No. 7,790,392; U.S. Pat. No. 7,501,092; U.S. Pat. No. 8,088,631.)
Upconverting luminescence refers to an anti-Stokes type process in which the sequential absorption of two or more photons leads to the emission of light at shorter wavelength (e.g., ultraviolet, visible, and near-infrared) than the excitation wavelength. For instance, Lanthanide ion (Ln3+) doped UCNPs are able to absorb near-infrared (NIR) photons and convert such low energy into shorter wavelength emissions. (Haase, et al. 2011 Angew Chem Int Edit 50, 5808.) Utilizing long-lived, ladder-like energy levels of Ln3+, the intensity of anti-Stokes luminescence of UCNPs is orders of magnitude more potent compared with those of conventional synthetic dyes or quantum dots (QDs). (Wang, et al. 2009 Chem Soc Rev 38, 976-989.)
In the past decade, NaYF4 based upconversion nanoparticles have been widely studied as optical bio-probes based on their advantages like low photo-degradation, non-photobleaching, deep tissue penetration and weak auto-fluorescence. (Chatterjee, et al. 2010 Small 6, 2781-2795.)
NIR emitting UCNPs have several additional advantages over more traditional fluorescent probes. For example, UCNPs are excited with a biocompatible NIR wavelength (980 nm), which is then upconverted to a higher energy for emission at a shorter NIR wavelength (800 nm). This NIRin-NIRout property permits less light scattering and greater tissue penetration for in vivo imaging because both excitation and emission wavelength are within the biological NIR optical transmission window (700-1000 nm). Moreover, the longer wavelength NIR light minimizes photo-induced damage. In addition, the spectral overlap with endogenous cellular fluorophores is significantly minimized, providing virtually zero auto-fluorescent background, which significantly enhances the signal-to-noise ratio. The nanoparticles are extremely photostable, making them ideal for longitude tracking experiments. UCNPs do not contain toxic elements of Class A (cadmium [Cd], mercury [Hg], lead [Pb]) and Class B (selenium [Se], arsenic [As]), offering great potential as biocompatible imaging probes for clinical applications. Finally, UCNPs can be made into dual optical/MRI probes by doping the same nanoparticle matrix containing lanthanide with the conventional MRI contrast element, gadolinium (Gd), thus synergizing the advantages of light- and magnetic resonance-imaging modalities.
Most photosensitizers are excited by visible or UV light, which has limited penetration depth due to the light absorption and scattering by biological tissues, resulting in ineffective diagnostic and therapeutic effects to internal or large tumors. UCNPs have the ability to convert NIR light to UV and visible photons, which can active photosensitizers adsorbed on nanoparticles via resonance energy transfer to generate reactive oxygen species (ROS) to kill cancer cells. It would provide a promising alternative to overcome hurdles of current photodynamic therapies.
However, UCNPs are hindered by the potential toxicity of the lanthanides. Moreover, most current protocols for synthesizing such UCNPs are not reliable and are not amenable to large-scale productions due to their inconvenient precursor pretreatments, multi-step phase-transitions, and/or long aging processes.
Wang et al. reported that a CaF2 shell can improve the upconversion luminescence of α-NaLnF4 UCNPs using a two-step reaction. (Wang, et al. 2012 Chem. Eur. J. 18, 5558-5564.) Yet, the byproduct of a water molecule from their high temperature reaction with the mixture of oleic acid and oleyl amine solvents lead to intense explosive boiling, and limiting the reproducibility of the synthesis and uniformity of the nanoparticle products. In addition, such a complicated two-step approach also hinders the further development of UCNPs in a high throughput manner.
Accordingly, there is an ongoing need for novel UCNPs and improved methods of syntheses and applications thereof, especially those that require biocompatibility.